As the use of killed whole or attenuated live vaccines of the previous century gives way to the use of more sophisticated subunit protein and DNA vaccines that will characterize vaccines in next several decades, finding safe and effective vaccine adjuvants is becoming increasingly important. Although the new generations of vaccines are more targeted by design, they are also far less immunogenic and typically require powerful adjuvants to induce sufficient immune responses in the human body. It has also been challenging to develop adjuvants with sufficient efficacy and safety to satisfy the stringent requirements of Western regulatory agencies.
The pace of vaccine adjuvant development has been slower in comparison to the rapid advance of vaccine development. Currently, very few chemical or biological adjuvants are approved for human use in the West. Aluminum salts (aluminum hydroxide, aluminum phosphate or alum) have been used in vaccine preparations for over 80 years (Glenny et al. 1926). They have the ability to create more antigenic precipitates with some vaccines, enhance the uptake by antigen-presenting cells by increasing the local concentration of antigen at the injection site, and stimulate immunogenicity by direct or indirect stimulation of dendritic cells, activation of complement, and by inducing the release of chemokines (Hogen Esch 2002). While these mechanisms can be relevant in stimulating type II (antibody-mediated) immune responses, they do not induce cytotoxic T-cell or cell-mediated immune responses. Aluminum salts also cause side effects in a certain percentage of the population that receives such vaccinations.
Recently, several additional adjuvants received regulatory approval in Europe. Monophosphoryl lipid A (MPL), a derivative of the lipopolysaccharides of the bacterial cell wall, was recently approved by the European Medicines Agency (EMEA) in the vaccine FENDRIX® (GlaxoSmithKline), a vaccine against hepatitis B. MPL, developed by Corixa (Seattle, Wash.), is an adjuvant in several other vaccines that are currently in clinical testing. The EMEA also recently approved the oil-in-water emulsion adjuvant MF59 for use with FOCETRIA®, a Novartis' pandemic influenza vaccine. Neither of these has received market approval by the FDA.
There are a wide number of substances that could potentially be used as adjuvants: haptens, hemocyanin, oil-in-water emulsions, surfactants, bacterial and viral components, HLA molecules, cytokines, toll receptor agonists, and heat shock proteins. Many of these are powerful immunostimulators that induce both type I and type II immune responses. However, most of these also have a high potential for side effects and have therefore not been approved for human use. Both the FDA and the EMEA have adopted requirements for vaccine adjuvants that are strict and have grown increasingly stringent in recent years. Fundamentally, this orientation is based on the fact that vaccines are used to prevent illness, not treat disease. The safety of a vaccine must be weighed against a hypothetical health threat, in comparison to therapies whose safety profiles are measured against the actual disease they are designed to treat. The result is that the presumption of safety is already far higher for vaccines.